Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Division of General Medicine and Primary Care, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Hum Mol Genet. 2022 Oct 20;31(R1):R123-R136. doi: 10.1093/hmg/ddac196.
Aberrant splicing underlies many human diseases, including cancer, cardiovascular diseases and neurological disorders. Genome-wide mapping of splicing quantitative trait loci (sQTLs) has shown that genetic regulation of alternative splicing is widespread. However, identification of the corresponding isoform or protein products associated with disease-associated sQTLs is challenging with short-read RNA-seq, which cannot precisely characterize full-length transcript isoforms. Furthermore, contemporary sQTL interpretation often relies on reference transcript annotations, which are incomplete. Solutions to these issues may be found through integration of newly emerging long-read sequencing technologies. Long-read sequencing offers the capability to sequence full-length mRNA transcripts and, in some cases, to link sQTLs to transcript isoforms containing disease-relevant protein alterations. Here, we provide an overview of sQTL mapping approaches, the use of long-read sequencing to characterize sQTL effects on isoforms, the linkage of RNA isoforms to protein-level functions and comment on future directions in the field. Based on recent progress, long-read RNA sequencing promises to be part of the human disease genetics toolkit to discover and treat protein isoforms causing rare and complex diseases.
异常剪接是许多人类疾病（包括癌症、心血管疾病和神经紊乱）的基础。全基因组剪接定量性状基因座（sQTL）图谱显示，选择性剪接的遗传调控广泛存在。然而，使用短读长 RNA-seq 难以识别与疾病相关 sQTL 相关的剪接异构体或蛋白质产物，因为短读长 RNA-seq 无法精确描述全长转录本异构体。此外，当代 sQTL 解释通常依赖于参考转录本注释，但这些注释并不完整。通过整合新兴的长读长测序技术，可以解决这些问题。长读长测序提供了对全长 mRNA 转录本进行测序的能力，并且在某些情况下，可以将 sQTL 与包含与疾病相关的蛋白质改变的转录本异构体联系起来。在这里，我们概述了 sQTL 映射方法，以及使用长读长测序来描述 sQTL 对异构体的影响、将 RNA 异构体与蛋白质水平功能联系起来，并对该领域的未来方向进行了评论。基于最近的进展，长读长 RNA 测序有望成为发现和治疗导致罕见和复杂疾病的蛋白质异构体的人类疾病遗传学工具包的一部分。
